The goal of this program project (PPG) is to prevent serious neurological disease in the elderly caused by reactivation of the ubiquitous highly neurotropic varicella zoster virus (VZV). The PPG contains 3 scientific projects and supportive administrative and scientific cores. Primary infection by varicella zoster virus (VZV) usually causes varicella, after which virus becomes latent in ganglionic neurons along the entire neuraxis. With aging, a declining cell-mediated immunity to VZV leads to virus reactivation, manifesting as herpes zoster (shingles) characterized by pain and rash restricted to 1-3 dermatomes. The incidence and severity of zoster is also increased in organ transplant recipients and patients with cancer or AIDS. Zoster is frequently complicated by chronic pain (postherpetic neuralgia), paralysis, blindness and stroke. Currently, -1,000,000 Americans develop zoster annually. Oka VZV vaccine reduces the incidence of zoster by 50%, but even if every American over age 60 was vaccinated, >500,000 cases would still occur every year. This PPG will: determine the emerging role of multifocal VZV vasculopathy as an important cause of vision loss and headaches in the elderly, examine mechanisms by which VZV exits latency to cause disease and identify key virus-host interactions involved in immunity and spread of infection. Project 1, an exciting new translational project, will identify clinical, laboratory and pathological features of a form of multifocal VZV vasculopathy that mimics giant cell arteritis (GCA), a cause of vision loss and headache in the elderly, findings that are likely to shift the current clinical practice paradigm. Project 2 tests the hypothesis that VZV reactivation initially involves generalized deregulation of latent gene transcription followed by conditions conducive to virus DNA replication and release of infectious virus. Project 3 uses an animal model to determine critical virus-host immune cell interactions that contribute to viral pathogenesis. The combined studies will provide valuable clinical, laboratory and pathological data needed to diagnose and treat a form of multifocal VZV vasculopathy that mimics giant cell arteritis and will provide the needed molecular groundwork for efforts to prevent the cascade of events leading to VZV reactivation, a cause of serious neurologic disease, particularly in the rapidly increasing elderly and immunocompromised populations. This proposal melds the skills and strategies of MDs, PhDs and DVMs with expertise in clinical neurology, molecular virology and immunology.